Here we seek to understand how genetic and environmental factors jointly influence the risk of developing two highly co-morbid neuropsychiatric disorders, Tourette's Syndrome (TS) and Obsessive- Compulsive Disorder (OCD). These disorders are of major public health importance owing to their profound personal and societal costs. Little is known for certain about their etiology, and treatment, detection and prevention strategies are not optimal or directed by knowledge of pathophysiology. In other psychiatric disorders (e.g., schizophrenia, bipolar disorder and autism), genomics has begun to deliver fundamental knowledge about genetic architecture, identify specific loci for biological follow-up and localize pathways altered in disease. We intend to realize these same advances for TS and OCD by markedly increasing the worldwide sample size for genomic analysis of both disorders, in a first step toward elucidating the fundamental biology of these related conditions. Four overlapping areas will be investigated in this project. First, we will discover genomic loci harboring common and rare variation associated with TS and OCD. We propose to quadruple the sample size of published TS and OCD genome-wide association studies (GWAS), in a rapid and cost-effective manner by utilizing archived blood spots from Denmark. Second, we will discover replicable structural variants (CNVs) associated with TS and OCD. Disease-associated CNVs are attractive causative mutations since, by altering gene dosage or structure, they provide a direction of effect and molecular mechanism. Third, we will identify shared genetic risk factors for TS, OCD and its major comorbidities. Here we test whether clinical comorbidity equates to genetic comorbidity. Finally, we will identify gene by environment interactions predisposing individuals to TS and OCD. We have access to a wealth of longitudinal medical registry data for every individual that will be genotyped in this study. This creates an extraordinary opportunity to identify gene by environment interactions. In sum, this project could add a high-impact understanding of how genetic and environmental factors jointly influence risk of TS and OCD, and lead to new mechanistic hypotheses.